US7947732B2 - Therapeutic substituted chlorocyclopentanols - Google Patents
Therapeutic substituted chlorocyclopentanols Download PDFInfo
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- US7947732B2 US7947732B2 US12/692,368 US69236810A US7947732B2 US 7947732 B2 US7947732 B2 US 7947732B2 US 69236810 A US69236810 A US 69236810A US 7947732 B2 US7947732 B2 US 7947732B2
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- WMXIMNGPOCPEAO-UHFFFAOYSA-N 1-chlorocyclopentan-1-ol Chemical class OC1(Cl)CCCC1 WMXIMNGPOCPEAO-UHFFFAOYSA-N 0.000 title 1
- 230000001225 therapeutic effect Effects 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 34
- 239000000203 mixture Substances 0.000 claims abstract description 26
- 230000004410 intraocular pressure Effects 0.000 claims description 41
- 208000010412 Glaucoma Diseases 0.000 claims description 14
- 150000003839 salts Chemical class 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 9
- 241000124008 Mammalia Species 0.000 claims description 5
- GAWIXWVDTYZWAW-UHFFFAOYSA-N C[CH]O Chemical group C[CH]O GAWIXWVDTYZWAW-UHFFFAOYSA-N 0.000 claims description 4
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 4
- 239000007788 liquid Substances 0.000 claims description 4
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- JYQQWQJCEUMXQZ-UHFFFAOYSA-N methyl cyanate Chemical compound COC#N JYQQWQJCEUMXQZ-UHFFFAOYSA-N 0.000 claims description 2
- 239000003814 drug Substances 0.000 abstract description 8
- 238000002560 therapeutic procedure Methods 0.000 abstract 1
- 230000036439 ocular surface hyperemia Effects 0.000 description 26
- 241000282472 Canis lupus familiaris Species 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 8
- 206010020772 Hypertension Diseases 0.000 description 8
- 230000001631 hypertensive effect Effects 0.000 description 7
- 241000282693 Cercopithecidae Species 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- GFJBIGBYDDGRMG-ZGFBMJKBSA-N 2-(diethylamino)ethyl 5-[3-[(1r,2r,3r,5r)-5-chloro-2-[2-(3,5-dichlorophenyl)ethyl]-3-hydroxycyclopentyl]propyl]thiophene-2-carboxylate Chemical compound S1C(C(=O)OCCN(CC)CC)=CC=C1CCC[C@@H]1[C@@H](CCC=2C=C(Cl)C=C(Cl)C=2)[C@H](O)C[C@H]1Cl GFJBIGBYDDGRMG-ZGFBMJKBSA-N 0.000 description 5
- BSCXGQXKCWFKPX-NCXUSEDFSA-N 5-[3-[(1r,2r,3r,5r)-5-chloro-2-[2-(3,5-dichlorophenyl)ethyl]-3-hydroxycyclopentyl]propyl]thiophene-2-carboxylic acid Chemical compound C([C@H]1[C@H](Cl)C[C@H]([C@@H]1CCC=1C=C(Cl)C=C(Cl)C=1)O)CCC1=CC=C(C(O)=O)S1 BSCXGQXKCWFKPX-NCXUSEDFSA-N 0.000 description 5
- 239000000651 prodrug Substances 0.000 description 5
- 229940002612 prodrug Drugs 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 0 [1*]C1=CC(CC[C@H]2C(O)C[C@@H](Cl)[C@@H]2CCCC2=CC=C([Y])S2)=CC([2*])=C1 Chemical compound [1*]C1=CC(CC[C@H]2C(O)C[C@@H](Cl)[C@@H]2CCCC2=CC=C([Y])S2)=CC([2*])=C1 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 150000002148 esters Chemical class 0.000 description 4
- 235000019439 ethyl acetate Nutrition 0.000 description 4
- 150000003180 prostaglandins Chemical class 0.000 description 4
- ONHDBJVQZHLNND-BGBTUJIRSA-N 2-(diethylamino)ethyl 5-[3-[(1r,2r,3r,5r)-5-chloro-2-[2-(3,5-dichlorophenyl)ethyl]-3-hydroxycyclopentyl]propyl]thiophene-2-carboxylate;hydrochloride Chemical compound Cl.S1C(C(=O)OCCN(CC)CC)=CC=C1CCC[C@@H]1[C@@H](CCC=2C=C(Cl)C=C(Cl)C=2)[C@H](O)C[C@H]1Cl ONHDBJVQZHLNND-BGBTUJIRSA-N 0.000 description 3
- ABVSNACOXNNDRK-KLHDSHLOSA-N 5-[3-[(1r,2r,3r,5r)-5-chloro-2-[2-(2,6-dichloropyridin-4-yl)ethyl]-3-hydroxycyclopentyl]propyl]thiophene-2-carboxylic acid Chemical compound C([C@H]1[C@H](Cl)C[C@H]([C@@H]1CCC=1C=C(Cl)N=C(Cl)C=1)O)CCC1=CC=C(C(O)=O)S1 ABVSNACOXNNDRK-KLHDSHLOSA-N 0.000 description 3
- FJAXHHUHWVUQNH-UAFMIMERSA-N 5-[3-[(1r,2r,3r,5r)-5-chloro-2-[2-[3-chloro-5-(hydroxymethyl)phenyl]ethyl]-3-hydroxycyclopentyl]propyl]thiophene-2-carboxylic acid Chemical compound OCC1=CC(Cl)=CC(CC[C@@H]2[C@H]([C@H](Cl)C[C@H]2O)CCCC=2SC(=CC=2)C(O)=O)=C1 FJAXHHUHWVUQNH-UAFMIMERSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 201000002862 Angle-Closure Glaucoma Diseases 0.000 description 3
- 230000001154 acute effect Effects 0.000 description 3
- 210000002159 anterior chamber Anatomy 0.000 description 3
- 210000001742 aqueous humor Anatomy 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000013626 chemical specie Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 229940094443 oxytocics prostaglandins Drugs 0.000 description 3
- WGJJROVFWIXTPA-OALUTQOASA-N prostanoic acid Chemical class CCCCCCCC[C@H]1CCC[C@@H]1CCCCCCC(O)=O WGJJROVFWIXTPA-OALUTQOASA-N 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- VBRZZVLWVBQOSE-BRSBDYLESA-N 5-[3-[(1r,2r,3r,5r)-5-chloro-2-[(3,5-dichlorophenyl)sulfanylmethyl]-3-hydroxycyclopentyl]propyl]thiophene-2-carboxylic acid Chemical compound C([C@H]1[C@H](Cl)C[C@H]([C@@H]1CSC=1C=C(Cl)C=C(Cl)C=1)O)CCC1=CC=C(C(O)=O)S1 VBRZZVLWVBQOSE-BRSBDYLESA-N 0.000 description 2
- BAPVMTWULFYJSV-BRSBDYLESA-N 5-[3-[(1r,2s,3r,5r)-5-chloro-2-[(3,5-dichloroanilino)methyl]-3-hydroxycyclopentyl]propyl]thiophene-2-carboxylic acid Chemical compound C([C@H]1[C@H](Cl)C[C@H]([C@@H]1CNC=1C=C(Cl)C=C(Cl)C=1)O)CCC1=CC=C(C(O)=O)S1 BAPVMTWULFYJSV-BRSBDYLESA-N 0.000 description 2
- 208000002177 Cataract Diseases 0.000 description 2
- 239000007832 Na2SO4 Substances 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- BSCXGQXKCWFKPX-MKXGPGLRSA-N O=C(O)C1=CC=C(CCC[C@H]2[C@H](Cl)C[C@H](O)[C@@H]2CCC2=CC(Cl)=CC(Cl)=C2)S1 Chemical compound O=C(O)C1=CC=C(CCC[C@H]2[C@H](Cl)C[C@H](O)[C@@H]2CCC2=CC(Cl)=CC(Cl)=C2)S1 BSCXGQXKCWFKPX-MKXGPGLRSA-N 0.000 description 2
- DXRSDZOXSKYJBJ-XRXFAXGQSA-N OCC1=CC=C(CCC[C@H]2[C@H](Cl)C[C@@H](O)[C@@H]2CCC2=CC(Cl)=CC(Cl)=C2)S1 Chemical compound OCC1=CC=C(CCC[C@H]2[C@H](Cl)C[C@@H](O)[C@@H]2CCC2=CC(Cl)=CC(Cl)=C2)S1 DXRSDZOXSKYJBJ-XRXFAXGQSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 201000001326 acute closed-angle glaucoma Diseases 0.000 description 2
- 125000002723 alicyclic group Chemical group 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 150000002066 eicosanoids Chemical class 0.000 description 2
- 230000004406 elevated intraocular pressure Effects 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- SBWJSUOROLFFFT-SSGKUCQKSA-N propan-2-yl 5-[3-[(1r,2r,3r,5r)-5-chloro-2-[2-[3-chloro-5-(hydroxymethyl)phenyl]ethyl]-3-hydroxycyclopentyl]propyl]thiophene-2-carboxylate Chemical compound S1C(C(=O)OC(C)C)=CC=C1CCC[C@@H]1[C@@H](CCC=2C=C(CO)C=C(Cl)C=2)[C@H](O)C[C@H]1Cl SBWJSUOROLFFFT-SSGKUCQKSA-N 0.000 description 2
- GMVPRGQOIOIIMI-DWKJAMRDSA-N prostaglandin E1 Chemical compound CCCCC[C@H](O)\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1CCCCCCC(O)=O GMVPRGQOIOIIMI-DWKJAMRDSA-N 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- PXGPLTODNUVGFL-BRIYLRKRSA-N (E,Z)-(1R,2R,3R,5S)-7-(3,5-Dihydroxy-2-((3S)-(3-hydroxy-1-octenyl))cyclopentyl)-5-heptenoic acid Chemical compound CCCCC[C@H](O)C=C[C@H]1[C@H](O)C[C@H](O)[C@@H]1CC=CCCCC(O)=O PXGPLTODNUVGFL-BRIYLRKRSA-N 0.000 description 1
- HLMHCDKXKXBKQK-UHFFFAOYSA-N 2-bromoethyl(diethyl)azanium;bromide Chemical compound Br.CCN(CC)CCBr HLMHCDKXKXBKQK-UHFFFAOYSA-N 0.000 description 1
- BXJDZUYSMZVSAA-ZWQPKGFESA-N 5-[3-[(1r,2r,3r,5r)-5-chloro-2-[(3,5-dichlorophenyl)sulfinylmethyl]-3-hydroxycyclopentyl]propyl]thiophene-2-carboxylic acid Chemical compound C([C@H]1[C@H](Cl)C[C@H]([C@@H]1CS(=O)C=1C=C(Cl)C=C(Cl)C=1)O)CCC1=CC=C(C(O)=O)S1 BXJDZUYSMZVSAA-ZWQPKGFESA-N 0.000 description 1
- REIIBADUXFMCCQ-NCXUSEDFSA-N 7-[(1r,2r,3r,5r)-5-chloro-2-[2-(3,5-dichlorophenyl)ethyl]-3-hydroxycyclopentyl]heptanoic acid Chemical compound O[C@@H]1C[C@@H](Cl)[C@H](CCCCCCC(O)=O)[C@H]1CCC1=CC(Cl)=CC(Cl)=C1 REIIBADUXFMCCQ-NCXUSEDFSA-N 0.000 description 1
- 229940121840 Beta adrenoreceptor antagonist Drugs 0.000 description 1
- 201000004569 Blindness Diseases 0.000 description 1
- BODMNALNPOXZGW-XRXFAXGQSA-N CC1=CC(C)=CC(CC[C@H]2[C@H](O)C[C@@H](Cl)[C@@H]2CCCC2=CC=C(C(=O)O)S2)=C1 Chemical compound CC1=CC(C)=CC(CC[C@H]2[C@H](O)C[C@@H](Cl)[C@@H]2CCCC2=CC=C(C(=O)O)S2)=C1 BODMNALNPOXZGW-XRXFAXGQSA-N 0.000 description 1
- 206010018325 Congenital glaucomas Diseases 0.000 description 1
- 206010012565 Developmental glaucoma Diseases 0.000 description 1
- 208000031969 Eye Hemorrhage Diseases 0.000 description 1
- 206010067684 Iris bombe Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 206010068960 Narrow anterior chamber angle Diseases 0.000 description 1
- VMEILLBYBVPGJU-NCXUSEDFSA-N O=C(O)C1=CC=C(CCC[C@H]2[C@H](Cl)C[C@@H](O)[C@@H]2CCC2=CC(F)=CC(F)=C2)S1 Chemical compound O=C(O)C1=CC=C(CCC[C@H]2[C@H](Cl)C[C@@H](O)[C@@H]2CCC2=CC(F)=CC(F)=C2)S1 VMEILLBYBVPGJU-NCXUSEDFSA-N 0.000 description 1
- NAIRQSUQMPSYAV-BRSBDYLESA-N O=C(O)C1=CC=C(CCC[C@H]2[C@H](Cl)C[C@@H](O)[C@@H]2CSC2=CC(F)=CC(F)=C2)S1 Chemical compound O=C(O)C1=CC=C(CCC[C@H]2[C@H](Cl)C[C@@H](O)[C@@H]2CSC2=CC(F)=CC(F)=C2)S1 NAIRQSUQMPSYAV-BRSBDYLESA-N 0.000 description 1
- BLLZJPGDBYLPLR-BRSBDYLESA-N O=C(O)C1=CC=C(CCC[C@H]2[C@H](Cl)C[C@@H](O)[C@@H]2C[SH](O)C2=CC(Cl)=CC(Cl)=C2)S1 Chemical compound O=C(O)C1=CC=C(CCC[C@H]2[C@H](Cl)C[C@@H](O)[C@@H]2C[SH](O)C2=CC(Cl)=CC(Cl)=C2)S1 BLLZJPGDBYLPLR-BRSBDYLESA-N 0.000 description 1
- 208000022873 Ocular disease Diseases 0.000 description 1
- 206010030348 Open-Angle Glaucoma Diseases 0.000 description 1
- 206010046851 Uveitis Diseases 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 239000002220 antihypertensive agent Substances 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 201000005667 central retinal vein occlusion Diseases 0.000 description 1
- 150000005829 chemical entities Chemical class 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 201000005682 chronic closed-angle glaucoma Diseases 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 230000010339 dilation Effects 0.000 description 1
- XEYBRNLFEZDVAW-ARSRFYASSA-N dinoprostone Chemical compound CCCCC[C@H](O)\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1C\C=C/CCCC(O)=O XEYBRNLFEZDVAW-ARSRFYASSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 230000006806 disease prevention Effects 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 238000009510 drug design Methods 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 210000000416 exudates and transudate Anatomy 0.000 description 1
- 239000003889 eye drop Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- -1 hydride ion Chemical class 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- CBOIHMRHGLHBPB-UHFFFAOYSA-N hydroxymethyl Chemical group O[CH2] CBOIHMRHGLHBPB-UHFFFAOYSA-N 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 239000008297 liquid dosage form Substances 0.000 description 1
- 208000018769 loss of vision Diseases 0.000 description 1
- 231100000864 loss of vision Toxicity 0.000 description 1
- 238000007726 management method Methods 0.000 description 1
- 230000000116 mitigating effect Effects 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000002250 progressing effect Effects 0.000 description 1
- PXGPLTODNUVGFL-JZFBHDEDSA-N prostaglandin F2beta Chemical compound CCCCC[C@H](O)\C=C\[C@H]1[C@H](O)C[C@@H](O)[C@@H]1C\C=C/CCCC(O)=O PXGPLTODNUVGFL-JZFBHDEDSA-N 0.000 description 1
- 210000001747 pupil Anatomy 0.000 description 1
- 208000004644 retinal vein occlusion Diseases 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 210000001585 trabecular meshwork Anatomy 0.000 description 1
- 230000008733 trauma Effects 0.000 description 1
- 230000004393 visual impairment Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
- C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
- C07D333/16—Radicals substituted by singly bound hetero atoms other than halogen by oxygen atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/06—Antiglaucoma agents or miotics
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/08—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing alicyclic rings
Definitions
- Ocular hypotensive agents are useful in the treatment of a number of various ocular hypertensive conditions, such as post-surgical and post-laser trabeculectomy ocular hypertensive episodes, glaucoma, and as presurgical adjuncts.
- Glaucoma is a disease of the eye characterized by increased intraocular pressure. On the basis of its etiology, glaucoma has been classified as primary or secondary. For example, primary glaucoma in adults (congenital glaucoma) may be either open-angle or acute or chronic angle-closure. Secondary glaucoma results from pre-existing ocular diseases such as uveitis, intraocular tumor or an enlarged cataract.
- the underlying causes of primary glaucoma are not yet known.
- the increased intraocular tension is due to the obstruction of aqueous humor outflow.
- chronic open-angle glaucoma the anterior chamber and its anatomic structures appear normal, but drainage of the aqueous humor is impeded.
- acute or chronic angle-closure glaucoma the anterior chamber is shallow, the filtration angle is narrowed, and the iris may obstruct the trabecular meshwork at the entrance of the canal of Schlemm. Dilation of the pupil may push the root of the iris forward against the angle, and may produce pupilary block and thus precipitate an acute attack. Eyes with narrow anterior chamber angles are predisposed to acute angle-closure glaucoma attacks of various degrees of severity.
- Secondary glaucoma is caused by any interference with the flow of aqueous humor from the posterior chamber into the anterior chamber and subsequently, into the canal of Schlemm.
- Inflammatory disease of the anterior segment may prevent aqueous escape by causing complete posterior synechia in iris bombe, and may plug the drainage channel with exudates.
- Other common causes are intraocular tumors, enlarged cataracts, central retinal vein occlusion, trauma to the eye, operative procedures and intraocular hemorrhage.
- glaucoma occurs in about 2% of all persons over the age of 40 and may be asymptotic for years before progressing to rapid loss of vision.
- topical ⁇ -adrenoreceptor antagonists have traditionally been the drugs of choice for treating glaucoma.
- Eicosanoids and their derivatives are currently commercially available for use in glaucoma management.
- Eicosanoids and derivatives include numerous biologically important compounds such as prostaglandins and their derivatives.
- Prostaglandins can be described as derivatives of prostanoic acid which have the following structural formula:
- prostaglandins are known, depending on the structure and substituents carried on the alicyclic ring of the prostanoic acid skeleton. Further classification is based on the number of unsaturated bonds in the side chain indicated by numerical subscripts after the generic type of prostaglandin [e.g. prostaglandin E 1 (PGE 1 ), prostaglandin E 2 (PGE 2 )], and on the configuration of the substituents on the alicyclic ring indicated by ⁇ or ⁇ [e.g. prostaglandin F 2 ⁇ (PGF 2 ⁇ )].
- PGE 1 prostaglandin E 1
- PGE 2 prostaglandin E 2
- PPF 2 ⁇ prostaglandin F 2 ⁇
- Y is CO 2 H or CH 2 OH
- R 3 is a C 3 alkyl. In a certain embodiment, R 3 is isopropyl.
- R 3 is hydroxyethyl
- R 3 is —CH 2 CH 2 —N(R 4 ) 2 . In a certain embodiment, R 3 is —CH 2 CH 2 —N(Et) 2 .
- the compound is incorporated into a dosage form or a medicament and administered to the mammal, such as a person, in need thereof.
- a liquid composition may be administered as an eye drop or a solid or liquid dosage form may also be administered orally.
- Other types of dosage forms and medicaments are well known in the art, and may also be used.
- compositions comprising a compound disclosed herein, wherein said composition is a liquid which is ophthalmically acceptable.
- Another embodiment is a medicament comprising a compound disclosed herein, wherein said medicament is a liquid which is ophthalmically acceptable.
- Another embodiment is a method comprising administering a compound disclosed herein to a mammal for the treatment of glaucoma or elevated intraocular pressure.
- kits comprising a composition comprising compound disclosed herein, a container, and instructions for administration of said composition to a mammal for the treatment of glaucoma or elevated intraocular pressure.
- treat refers to the use of a compound, composition, therapeutically active agent, or drug in the diagnosis, cure, mitigation, treatment, or prevention of disease or other undesirable condition.
- reference to a compound should be construed broadly to include pharmaceutically acceptable salts, prodrugs, tautomers, alternate solid forms, non-covalent complexes, and combinations thereof, of a chemical entity of the depicted structure or chemical name.
- a pharmaceutically acceptable salt is any salt of the parent compound that is suitable for administration to an animal or human.
- a pharmaceutically acceptable salt also refers to any salt which may form in vivo as a result of administration of an acid, another salt, or a prodrug which is converted into an acid or salt.
- a salt comprises one or more ionic forms of the compound, such as a conjugate acid or base, associated with one or more corresponding counter-ions. Salts can form from or incorporate one or more deprotonated acidic groups (e.g. carboxylic acids), one or more protonated basic groups (e.g. amines), or both (e.g. zwitterions).
- a prodrug is a compound which is converted to a therapeutically active compound after administration. For example, conversion may occur by hydrolysis of an ester group or some other biologically labile group.
- Prodrug preparation is well known in the art. For example, “Prodrugs and Drug Delivery Systems,” which is a chapter in Richard B. Silverman, Organic Chemistry of Drug Design and Drug Action, 2d Ed., Elsevier Academic Press: Amsterdam, 2004, pp. 496-557, provides further detail on the subject.
- Tautomers are isomers that are in rapid equilibrium with one another.
- tautomers may be related by transfer of a proton, hydrogen atom, or hydride ion.
- Alternate solid forms are different solid forms than those that may result from practicing the procedures described herein.
- alternate solid forms may be polymorphs, different kinds of amorphous solid forms, glasses, and the like.
- Non-covalent complexes are complexes that may form between the compound and one or more additional chemical species that do not involve a covalent bonding interaction between the compound and the additional chemical species. They may or may not have a specific ratio between the compound and the additional chemical species. Examples might include solvates, hydrates, charge transfer complexes, and the like.
- composition and dosage regimen of example 1 was also tested in laser-induced hypertensive monkeys, using one single day dose. At 0.01%, the maximum IOP decrease from baseline was 13.9 mmHg (40%) at 24 h.
- composition and dosage regimen of example 1 may also be used to reduce IOP in humans.
- the composition of Example 4 may be used to reduce IOP in a person by administering the composition once a day to the person.
- the maximum intraocular pressure (IOP) decrease from baseline was 5.6 mmHg (36%) at 54 h; the maximum ocular surface hyperemia (OSH) score was 1.75 at 50 h.
- the maximum intraocular pressure (IOP) decrease from baseline was 3.6 mmHg (24%) at 76 h; the maximum ocular surface hyperemia (OSH) score was 0.8 at 74 h.
- compositions of Example 6 may be used to reduce IOP in a person by administering the composition once a day to the person.
- compositions of Example 9 may be used to reduce IOP in a person by administering the composition once a day to the person.
- compositions of Example 11 may be used to reduce IOP in a person by administering the composition once a day to the person.
- Isopropyl 5-(3-((1R,2R,3R,5R)-5-chloro-2-(3-chloro-5-(hydroxymethyl)phenethyl)-3-hydroxycyclopentyl)propyl)thiophene-2-carboxylate was tested in normotensive dogs at 0.001%, dosing once daily for 5 days.
- the maximum intraocular pressure (IOP) decrease from baseline was 2.8 mmHg (17%) at 4 h; the maximum ocular surface hyperemia (OSH) score was 0.9 at 26 h.
- Isopropyl 5-(3-((1R,2R,3R,5R)-5-chloro-2-(3-chloro-5-(hydroxymethyl)phenethyl)-3-hydroxycyclopentyl)propyl)thiophene-2-carboxylate was also tested in laser-induced hypertensive monkeys, using one single day dose. At 0.001%, the maximum IOP decrease from baseline was 9.2 mmHg (24%) at 24 h.
- compositions of Examples 1-18 may be used to reduce IOP in a person by administering the composition once a day to the person.
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- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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| AU2011207352A AU2011207352B2 (en) | 2010-01-22 | 2011-01-21 | Therapeutic substituted chlorocyclopentanols |
| EP11702104.8A EP2526094B1 (de) | 2010-01-22 | 2011-01-21 | Substituierte chlorocyclopentanole für therapeutische zwecke |
| CA2787782A CA2787782C (en) | 2010-01-22 | 2011-01-21 | Therapeutic substituted chlorocyclopentanols |
| PCT/US2011/022089 WO2011091276A1 (en) | 2010-01-22 | 2011-01-21 | Therapeutic substituted chlorocyclopentanols |
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| US94962707P | 2007-07-13 | 2007-07-13 | |
| US12/111,727 US7662850B2 (en) | 2007-07-13 | 2008-04-29 | Therapeutic substituted chlorocyclopentanols |
| US12/692,368 US7947732B2 (en) | 2007-07-13 | 2010-01-22 | Therapeutic substituted chlorocyclopentanols |
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| CA (1) | CA2787782C (de) |
| WO (1) | WO2011091276A1 (de) |
Cited By (4)
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| US20110059939A1 (en) * | 2008-05-09 | 2011-03-10 | Allergan ,Inc | Therapeutic compounds |
| US20150336924A1 (en) * | 2014-05-22 | 2015-11-26 | Allergan, Inc. | Amidoalkylenyl and amidoaryl esters, compositions thereof, and methods for their use |
| US9540357B1 (en) | 2014-07-31 | 2017-01-10 | Allergan, Inc. | 15-aryl prostaglandins as EP4 agonists, and methods of use thereof |
| US20170081304A1 (en) * | 2014-05-12 | 2017-03-23 | Allergan, Inc. | Quaternary ammonium alkyl esters as stable prodrugs |
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| US7993634B2 (en) | 2004-04-30 | 2011-08-09 | Allergan, Inc. | Oil-in-oil emulsified polymeric implants containing a hypotensive lipid and related methods |
| US7799336B2 (en) | 2004-04-30 | 2010-09-21 | Allergan, Inc. | Hypotensive lipid-containing biodegradable intraocular implants and related methods |
| US8722097B2 (en) | 2004-04-30 | 2014-05-13 | Allergan, Inc. | Oil-in-water method for making polymeric implants containing a hypotensive lipid |
| US9498457B2 (en) | 2004-04-30 | 2016-11-22 | Allergan, Inc. | Hypotensive prostamide-containing biodegradable intraocular implants and related implants |
| US8673341B2 (en) | 2004-04-30 | 2014-03-18 | Allergan, Inc. | Intraocular pressure reduction with intracameral bimatoprost implants |
| US20100247606A1 (en) * | 2009-03-25 | 2010-09-30 | Allergan, Inc. | Intraocular sustained release drug delivery systems and methods for treating ocular conditions |
| US9090595B2 (en) | 2012-08-27 | 2015-07-28 | Allergan, Inc. | Reduced central corneal thickening by use of hydrophilic ester prodrugs of beta-chlorocyclopentanes |
| JP6270848B2 (ja) | 2012-08-27 | 2018-01-31 | アラーガン、インコーポレイテッドＡｌｌｅｒｇａｎ，Ｉｎｃｏｒｐｏｒａｔｅｄ | ベータ−クロロシクロペンタンの親水性エステルプロドラッグの使用による角膜中央部肥厚の低下 |
| AU2015259752B2 (en) * | 2014-02-20 | 2019-06-20 | Allergan, Inc. | Reduced central corneal thickening by use of hydrophilic ester prodrugs of beta-chlorocyclopentanes |
| US10329284B2 (en) | 2014-10-02 | 2019-06-25 | Allergan, Inc. | Ester prodrugs of gamma-lactams and their use |
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| US20100247606A1 (en) * | 2009-03-25 | 2010-09-30 | Allergan, Inc. | Intraocular sustained release drug delivery systems and methods for treating ocular conditions |
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2010
- 2010-01-22 US US12/692,368 patent/US7947732B2/en active Active
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- 2011-01-21 WO PCT/US2011/022089 patent/WO2011091276A1/en not_active Ceased
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- 2011-01-21 AU AU2011207352A patent/AU2011207352B2/en not_active Ceased
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| US20110059939A1 (en) * | 2008-05-09 | 2011-03-10 | Allergan ,Inc | Therapeutic compounds |
| US8569349B2 (en) * | 2008-05-09 | 2013-10-29 | Allergan, Inc. | Therapeutic compounds |
| US20170081304A1 (en) * | 2014-05-12 | 2017-03-23 | Allergan, Inc. | Quaternary ammonium alkyl esters as stable prodrugs |
| US9981938B2 (en) * | 2014-05-12 | 2018-05-29 | Allergan, Inc. | Quaternary ammonium alkyl esters as stable prodrugs |
| US20150336924A1 (en) * | 2014-05-22 | 2015-11-26 | Allergan, Inc. | Amidoalkylenyl and amidoaryl esters, compositions thereof, and methods for their use |
| US9573926B2 (en) * | 2014-05-22 | 2017-02-21 | Allergan, Inc. | Amidoalkylenyl and amidoaryl esters, compositions thereof, and methods for their use |
| US9540357B1 (en) | 2014-07-31 | 2017-01-10 | Allergan, Inc. | 15-aryl prostaglandins as EP4 agonists, and methods of use thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CA2787782A1 (en) | 2011-07-28 |
| WO2011091276A1 (en) | 2011-07-28 |
| US20100210689A1 (en) | 2010-08-19 |
| EP2526094B1 (de) | 2016-05-25 |
| AU2011207352A1 (en) | 2012-08-09 |
| CA2787782C (en) | 2018-03-13 |
| AU2011207352B2 (en) | 2016-05-26 |
| EP2526094A1 (de) | 2012-11-28 |
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